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Reading assignments: Katzung’s Basic & Clinical Pharmacology, 13th Edi ,Ch-52&53,p886-917; Dr.Sanjib Das • IV.Antiparasitic Chemotherapy: • A.Basic Principles of Antiparasitic Chemotherapy • B.Antiprotozoal Chemotherapy • 1. Antimalarials – Know the infectious cycles of the Plasmodia and which stages are susceptible to different antimalarials – Understand the effect of drug resistance on the clinical use of antimalarials • 2. Other antiprotozoal drugs – Know the mechanism of action, clinical uses, and adverse effects associated with these drugs • C. Anthelminthic Agents – Know mechanisms of action against intestinal and extra-intestinal parasites – Know drugs used clinically in North America (limit to infections by Ascaris, pinworm, hookworm, tapeworm) 1. Antimalarials ARTEMISININ CHLOROQUINE MEFLOQUINE PRIMAQUINE PYRIMETHAMINE-SULFADOXINE (FANSIDAR) 2. Anti-protozoal drugs METRONIDAZOLE TRIMETHOPRIM-SULFAMETHOXAZOLE PYRIMETHAMINE-SULFONAMIDE PENTAMIDINE Anti-Parasitic Chemotherapy: AntiMalarials Four species of protozoan-– – – – Plasmodium falciparum Plasmodium malariae Plasmodium vivax Plasmodium ovale • First two single cycle, second two multiple cycles • Key point-- Several drugs affect blood schizonts, only primaquine affects tissue schizonts Life cycle of malaria parasites https://www.youtube.com/watch?v=qMNmOsl5_e4 Anti-Malarials: Chloroquine Mechanism • Alters metabolism of hemoglobin by parasite, also blocks nucleic acid synthesis Pharmacokinetics • Oral or parenteral • Rapid, complete absorption; wide distribution • Excreted in urine, 25% as metabolite • Loading dose necessary for acute treatment Clinical Uses • "Highly effective blood schizonticide“ • Acute-- Clears parasitemia from all four Plasmodia – Curative for P. malariae and P. falciparum – Used with primaquine for P. vivax and P. ovale • Prophylactic-- Begin 1 week before travel, continue four weeks after return – Preferred drug for prophylaxis against all four species Chloroquine Adverse Effects-• Generally well tolerated • GI, mild headache; may exacerbate psoriasis or porphyria • Visual impairment occurs with long-term or high-dose therapy Resistance-• Widespread in South America, Africa, Asia • "P-glycoprotein" pumping mechanism • Block with verapamil in vitro Anti-Malarial Chemotherapy Mefloquine Mechanism unknown Pharmacokinetics • Only oral-- too irritating for parenteral • Well absorbed and distributed • Metabolized in liver, excreted in feces Adverse effects—CNS, possible psychotropic effects Clinical Uses-• Chloroquine-resistant malaria Fansidar (Pyrimethamine-Sulfadoxine)-• Anti-folate combination, typical effects Pharmacokinetics • Well absorbed and distributed, Excreted in urine Clinical Use-• Effective blood schizonticide for P. falciparum • Slow-acting; cannot be used alone for acute attacks Multi-drug resistance to fansidar and chloroquine common Anti-Malarial Chemotherapy • Atovaquone plus proguanil – Mechanism of action (1) Atovaquone selectively inhibits parasite mitochondrial electron transport (2) Proguanil’s metabolite cycloguanil, inhibits dihydrofolate reductase – Used to prevent or treat acute, uncomplicated P. falciparum malaria – Adverse effects (1) GI distress (2) Increased hepatic transaminase (3) Headache (4) Dizziness • Quinine and Quinidine – Still used to treat uncomplicated chloroquine-resistant P. falciparum malaria – Cinchonism (1) Overdose of quinine or its natural source, cinchona bark (2) Symptoms (a) Flushed and sweaty skin (b) Ringing of the ears (tinnitus) (c) Blurred vision (d) Impaired hearing (e) Confusion Anti-Malarial Chemotherapy: Tissue Schizonticides Primaquine-• Tissue schizonticide • Oral, well absorbed and distributed, extensively metabolized • Metabolites are intracellular oxidants • Used in combination with chloroquine for prophylaxis or cure of P. vivax, P. ovale • GI distress, hemolytic anemia in G6PDH deficiency Artemisinin— • Traditional Chinese medicine • Oral, very short t ½ • Activated by oxidative metabolism—free radicals, alkylation • Rapidly-acting blood schizonticide—particularly useful for multi-drug resistant P. falciparum Other Anti-Protozoal Drugs: Metronidazole & Tinidazole Mechanism • • • Tissue amebicide Nitroimidazole-- activated by electron donation & produce free radicals as MOA. Particularly effective for anaerobic/hypoxic sites Pharmacokinetics • Oral or IV • Well absorbed and distributed, including CNS, bone • Cleared in urine following hepatic metabolism Protozoa Clinical Uses • Urogenital trichomoniasis (Trichomonas vaginalis) Bacteria • Giardiasis (Giardia) • Amebiasis (Entamoeba histolytica) • Aspiration pneumonia • Anaerobic bacterial infections below diaphragm (including Clostridium difficile, Bacteroides fragilis ,Gardinella vaginalis & Acne Rosacea). • H. Pylori {used with bismuth & amoxycillin (or tetracycline) as ‘triple therapy’}. Adverse Effects • Nausea, headache, Dry mouth, • Stomatitis, metallic taste, leukopenia, cystitis, Reversible peripheral neuropathy (free redical injury) • Disulfiram effect A 21-year-old female is taking medication for a recently diagnosed medical problem. While at a college party, she develops facial flushing, headache, nausea, vomiting, and abdominal cramps immediately after having an alcoholic drink. This patient is most likely being treated for which conditions? Other Anti-Protozoal Drugs: Pentamidine Mechanism -- unknown Pharmacokinetics • IV, IM or aerosol • Concentrates in liver, spleen, kidneys • Slowly released from those sites • Doesn't enter CNS Clinical Use • Aerosol used for treatment/prophylaxis against Pneumocystis pneumonia (PCP) Adverse Effects • Can cause respiratory stimulation followed by depression; hypotension, anemia • Adverse effects less common with aerosol administration Other Anti-Protozoal Drugs: • Iodoquinol – Used for the local treatment of acute and chronic intestinal amebiasis – Used for asymptomatic cyst passers • Paromomycin – An aminoglycoside – Acts locally on ameba – Used to treat acute and chronic intestinal amebiasis 3. Anthelminthic drugs ALBENDAZOLE IVERMECTIN PRAZIQUANTEL THIABENDAZOLE MEBENDAZOLE PYRANTEL PAMOATE Anti-Helmintic Chemotherapy • Target is multi-cellular organism • Mobility/contractile systems in parasites are important targets Mebendazole-• Wide spectrum anti-helmintic • Given orally, less than 10% absorbed • Rapidly metabolized, excreted in urine • Mechanism-- Blocks microtubule synthesis, blocks vesicle and organelle movement • Effective against pinworm, hookworm, Ascaris • Dose limited by GI effects; Possibly embryotoxic Anti-Helmintic Chemotherapy Albendazole-• Wide spectrum anti-helmintic • Rapidly and completely metabolized in liver, conjugates excreted in urine • Interferes with microtubule aggregation, alters glucose uptake Praziquantel-• Effective treatment for all schistosomes, some trematodes and cestodes • 80% bioavailability after oral dosing • Rapidly and extensively metabolized, cleared in urine • Parent is active species • Increases membrane permeability to Ca2+,resulting in contraction and paralysis • Headache, dizziness, drowsiness may occur Anti-Helmintic Chemotherapy Thiabendazole and mebendazole • Mechanism of action: block microtubule formation • Uses – Thiabendazole (broad spectrum):, cutaneous larva migrans, strongyloidiasis (alternative drug) – Mebendazole: ascariasis, trichuriasis, hookworm, pinworm (Enterobius vermicularis), cysticercosis (Taenia solium), Echinococcus infestations • Adverse effects: abdominal pain, diarrhea Anti-Helmintic Chemotherapy Pyrantel pamoate • Mechanism of action – Acts as a depolarizing neuromuscular blocking agent on the nicotinic receptor – Increases the effects of acetylcholine and inhibits cholinesterase in the worm • Uses: ascariasis, pinworm (E. vermicularis), hookworm, whipworm (Trichuris trichiura), Trichostrongylus • Adverse effects: nausea, vomiting, diarrhea, anorexia Ivermectin • Mechanism of action: increases chloride permeability, thus polarizing cells, which leads to paralysis • Uses: strongyloidiasis, onchocerciasis Chemotherapeutic agents Antibacterial agents Antifungal agents Antiparasitic agents Antitumor agents Antiviral agents Amphotericin B Liposomal Ampho-B Flucytosine Antimalarials Ketoconazole Fluconazole Itraconazole Chloroquine Mefloquine Primaquine Anthelmintic drugs GABA Ivermectin strongyloidiasis tremetodes & Ca Praziquantel cestodes Tub Thiabendazole Tub Mebendazole Ach Pyrantel pamoate Griseofulvin Terbinafine Antiprotozoal drugs Metronidazole TrimethoprimSulfamethoxazole PyrimethamineSulfadoxine Pentamidine PCP A 55-year-old construction worker had a mild respiratory infection with flu-like symptoms that resolved in less than 2 weeks. Two months later, a chest radiograph revealed numerous diffuse calcific densities confirming a diagnosis of primary histoplasmosis. Which of the following binds to ergosterol and would be appropriate for treating this patient? A. B. C. D. E. Amphotericin B Flucytosine Itraconazole Nystatin Terbinafine Answer: A Amphotericin B & nystatin bind to ergosterol; toxicity due to binding to cholesterol in host cells A 39-year-old woman has dermatis and pneumonitis with eosinophilia caused by Strongyloides stercoralis (strongyloidiasis). Which of the following medications will paralyze the worm by intensifying GABAmediated transmission in the worm and would be appropriate for treating the condition of this patient? A. B. C. D. E. Chloroquine Ivermectin Praziquantel Primaquine Thiabendazole Answer: B Ivermectin paralyzes worms by increasing chloride permeability PowerPoint Slides Several of the PowerPoint slides are Copyright © 2002-04, the American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved. Some of slides in this session are from the above mentioned format and are free for use by members of ASPET. Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA). Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated whenever necessary